Page 287 - Color_Atlas_of_Physiology_5th_Ed._-_A._Despopoulos_2003

Cellular Transmission of Signals from GTP (cytosolic cAMP concentration rises) and
Extracellular Messengers inhibited by α i-GTP (cAMP concentration falls;
! A3).
Hormones, neurotransmitters (! p. 55 and
p. 82), cytokines and chemokines (! p. 94ff.) G s-activating messengers. ACTH, adenosine (A 2A
and A 2B rec.), antidiuretic hormone = vasopressin (V 2
act as messenger substances (first messengers) rec.), epinephrine and norepinephrine (" 1, " 2, " 3
that are transported to their respective target adrenoceptors), calcitonin, CGRP, CRH, dopamine
cells by extracellular pathways. The target cell (D 1 and D 5 rec.), FSH, glucagon, histamine (H 2 rec.),
has a high-affinity binding site (receptor) for oxytocin (V 2 rec., see above), many prostaglandins
its specific messenger substance. (DP, IP, EP 2 and EP 4 rec.), serotonin = 5-hydroxytrypt-
amine (5-HT 4 and 5-HT 7 rec), secretin and VIP acti-
Hormones and Reproduction protein-protein interactions (and sometimes messenger substances also activate G i proteins
Glycoprotein and peptide messengers as
vate G s proteins, thereby raising cAMP levels. TRH
well as catecholamines bind to cell surface re-
and TSH induce partial activation.
ceptors on the target cell. Binding of the mes-
G i-activating messengers. Some of the above
senger to its receptor usually triggers certain
(thereby lowering cAMP levels) using a different
protein-phospholipid interactions). This leads
binding receptor. Acetylcholine (M 2 and M 4 rec.),
adenosine (A l and A 3 rec.), epinephrine and norepi-
to the release of secondary messenger sub-
nephrine
angiotensin
II,
adrenoceptors),
stances (second messengers) that forward the
(α 2
chemokines, dopamine (D 2, D 3 and D 4 rec.), GABA
signal within the cell. Cyclic adenosine mono-
rec.), melatonin, neuropeptide Y, opioids, serotonin
phosphate
inositol
1,4,5-tris-
(cGMP),
= 5-hydroxytryptamine (5-HT l rec.), somatostatin
phosphate (IP 3), 1,2-diacylglycerol (DAG) and
and various other substances activate G i proteins.
11 phosphate (cAMP), cyclic guanosine mono- (GABA B rec.), glutamate (mGLU 2–4 and mGLU 6–8
Ca
are such second messengers. Since the
2+
molecular structure of the receptor ensures Effects of cAMP. cAMP activates type A protein
that the effect of the first messenger will be kinases (PKA = protein kinase A) which then
specific, multiple first messengers can use the activate other proteins (usually enzymes and
same second messenger. Moreover, the intra- membrane proteins, but sometimes the recep-
cellular concentration of the second mes- tor itself) by phosphorylation (! A4). The
senger can be raised by one messenger and specific response of the cell depends on the
lowered by another. In many cases, different type of protein phosphorylated, which is de-
types of receptors exist for a single first mes- termined by the type of protein kinases pres-
senger. ent in the target cell. Phosphorylation converts
the proteins from an inactive to an active form
cAMP as a Second Messenger or vice versa.
For a cAMP-mediated response to occur, the Hepatic glycogenolysis, for instance, is dually in-
cell membrane must contain stimulatory (G s) creased by cAMP and PKA. Glycogen synthase cata-
or inhibitory (G i) G proteins (guanyl nu- lyzing glycogen synthesis is inactivated by phospho-
cleotide-binding proteins) (! A1). These G rylation whereas glycogen phosphorylase stimulat-
proteins consist of three subunits—alpha (α S or ing glycogenolysis is activated by cAMP-mediated
α i), beta (") and gamma (γ)—and are therefore phosphorylation.
heterotrimers. Guanosine diphosphate (GDP) is Signal transduction comprises the entire sig-
bound to the α-subunit of an inactive naling pathway from the time the first mes-
G protein. Once the first messenger (M) binds senger binds to the cell to the occurrence of
to the receptor (Rec.), the M–Rec. complex cellular effect, during which time the signal
conjugates with the G s-GDP (or G i-GDP) can be (a) modified by other signals and
molecule (! A2). GDP is then replaced by cyto- (b) amplified by many powers of ten. A single
solic GTP, and the "γ-subunit and the M–Rec. adenylate cyclase molecule can produce
complex dissociate from the α-subunit if Mg 2+ numerous cAMP and PKA molecules, which in
is present (! A3). α s-GTP or α i-GTP remain as turn can phosphorylate an enormous number
the final products. Adenylate cyclase on the in- of enzyme molecules. The interposition of
274 side of the cell membrane is activated by α s- more kinases can lead to the formation of long
Despopoulos, Color Atlas of Physiology © 2003 Thieme !
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